Formulation for inhibiting formation of 5-ht2b agonists and methods of using same

Abstract

Drug combinations and their use are disclosed. A first drug is administered in combination with a second drug. The first drug such as fenfluramine is characterized by the formation of a metabolite including 5-HT2B agonists such as norfenfluramine with known adverse side effects. The second drug is in the form of a CYP inhibitor such as cannabidiol which modulates the formation of metabolite down thereby making the first drug safer.

1 .- 20 . (canceled) 
     
     
         21 . A method of treating a patient for a refractory epilepsy comprising, co-administering fenfluramine and stiripentol to the patient,
 wherein the dose of fenfluramine is reduced by at least 30% less than 0.8 mg/kg/day,   and wherein the reduced dose maintains the efficacy of fenfluramine and reduces the patient's exposure to norfenfluramine.   
     
     
         22 . The method of  claim 21  wherein the dose of fenfluramine is reduced by at least 40% less than 0.8 mg/kg/day. 
     
     
         23 . The method of  claim 21  wherein the dose of fenfluramine is reduced by at least 50% less than 0.8 mg/kg/day. 
     
     
         24 . The method of  claim 21  wherein the dose of fenfluramine is reduced by at least 60% less than 0.8 mg/kg/day. 
     
     
         25 . The method of  claim 21  wherein the dose of fenfluramine is reduced by at least 70% less than 0.8 mg/kg/day. 
     
     
         26 . The method of  claim 21 , wherein the refractory epilepsy is selected from the group consisting of Dravet syndrome, Lennox Gastaut syndrome, Doose syndrome and West syndrome. 
     
     
         27 . The method of  claim 21 , further comprising:
 co-administering clobazam.   
     
     
         28 . The method of  claim 21 , wherein the refractory epilepsy is Dravet syndrome. 
     
     
         29 . The method of  claim 21 , further comprising:
 co-administering to the patient an effective amount of an additional agent selected from the group consisting of acetazolamide, barbexaclone, beclamide, brivaracetam, buproprion, cinacalet, clobazam, clonazepam, clorazepate, diazepam, divaloprex, eslicarbazepine acetate, ethadione, ethotoin, felbamate, gabapentin, lacosamide, lorazepam, mephenytoin, methazolamide, methsuximide, methylphenobarbitol, midazolam, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, perampanel, piracetam, phenacemide, pheneturide, phensuximide, phenytoin, potassium bromide, pregabalin, primidone, retigabine, rufinamide, selectracetam, sodium valproate, sultiame, temazepam, tiagabine, topiramate, trimethadione, valnoctamide, valpromide, vigabatrin, zonisamide, and pharmaceutically acceptable salts thereof.   
     
     
         30 . A method of treating a patient for a refractory epilepsy comprising, co-administering fenfluramine and stiripentol to the patient,
 wherein the dose of fenfluramine is reduced by at least 30% less than an effective dose for the patient in the absence of the stiripentol,   and wherein the reduced dose maintains the efficacy of fenfluramine and reduces the patient's exposure to norfenfluramine.   
     
     
         31 . The method of  claim 30 , wherein the refractory epilepsy is selected from the group consisting of Dravet syndrome, Lennox Gastaut syndrome, Doose syndrome and West syndrome. 
     
     
         32 . The method of  claim 30 , further comprising:
 co-administering clobazam.   
     
     
         33 . A method of treating a patient for a refractory epilepsy comprising, co-administering fenfluramine and stiripentol to the patient,
 wherein the dose of fenfluramine is in an oral formulation and the fenfluramine is reduced by at least 40% less than an effective dose for the patient in the absence of the stiripentol,   and wherein the reduced dose maintains the efficacy of fenfluramine and reduces the patient's exposure to norfenfluramine.   
     
     
         34 . The method of  claim 33 , wherein the refractory epilepsy is selected from the group consisting of Dravet syndrome, Lennox Gastaut syndrome, Doose syndrome and West syndrome. 
     
     
         35 . The method of  claim 33 , further comprising:
 co-administering clobazam.   
     
     
         36 . The method of  claim 33 , wherein the refractory epilepsy is Dravet syndrome. 
     
     
         37 . The method of  claim 33 , further comprising:
 co-administering to the subject an effective amount of an additional agent selected from the group consisting of acetazolamide, barbexaclone, beclamide, brivaracetam, buproprion, cinacalet, clobazam, clonazepam, clorazepate, diazepam, divaloprex, eslicarbazepine acetate, ethadione, ethotoin, felbamate, gabapentin, lacosamide, lorazepam, mephenytoin, methazolamide, methsuximide, methylphenobarbitol, midazolam, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, perampanel, piracetam, phenacemide, pheneturide, phensuximide, phenytoin, potassium bromide, pregabalin, primidone, retigabine, rufinamide, selectracetam, sodium valproate, sultiame, temazepam, tiagabine, topiramate, trimethadione, valnoctamide, valpromide, vigabatrin, zonisamide, and pharmaceutically acceptable salts thereof.